PO.MCB02.02 · 分子与细胞生物学
一种可溶性Elesclomol类似物在体内选择性诱导铜死亡
Selective induction of cuproptosis in vivo by a soluble Elesclomol analog
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
由特定离子载体诱导的铜过载可触发铜死亡（cuproptosis），这是一种新近定义的调控性细胞死亡形式，为靶向癌症提供了一种新策略。虽然这一机制在培养细胞中已得到充分表征，但其在体内的相关性及治疗应用潜力仍不明确。表征最充分的离子载体elesclomol（ES）此前曾在临床试验中被检验，成效有限；然而，这些研究是在未了解或未考虑其铜结合机制或其诱导铜死亡能力的情况下进行的。在此，我们界定了ES在体内诱导铜死亡的生物学和药理学决定因素，以指导设计一种更有效且更耐受的ES类似物。我们首先确立了预先结合的ES（ES-Cu）比单独的ES更强效、药理活性更高，其在培养中维持靶向性铜死亡活性，并在异种移植模型中显示出更优的疗效。尽管ES-Cu治疗产生了显著的肿瘤应答，但未实现完全消退。为揭示限制应答的机制，我们进行了全基因组规模的ORF过表达筛选，鉴定出CYP11A1和CYP27A1（FDX1的线粒体伙伴）为耐药因素。这些发现表明，单独的FDX1表达不足以决定敏感性，有效的铜死亡需要FDX1活性与CYP代谢解偶联，这一关系也可能保护FDX1高表达的器官（如肾上腺和肾脏）免于毒性。为进一步克服ES溶解性差和药代动力学局限，我们合成了一种新的铜-ES类似物，其表现出改善的溶解性、增强的抗肿瘤疗效和降低的全身毒性。多重成像证实肿瘤内脂酰化蛋白的聚集，与靶向性铜死亡诱导一致。总体而言，这些发现揭示了FDX1-CYP偶联在调控铜死亡敏感性中此前未被认识的作用，并为基于铜离子载体的癌症疗法的生物标志物指导性开发指明了路径。
查看英文原文 English abstract
Copper overload induced by specific ionophores can trigger cuproptosis, a newly defined form of regulated cell death that offers a novel strategy to target cancer. While this mechanism has been well characterized in cultured cells, its relevance in vivo and potential for therapeutic use remain unclear. The best-characterized ionophore, elesclomol (ES), had been previously tested in clinical trials with limited success; however, these studies were conducted without knowledge or consideration of its copper-binding mechanism or its ability to induce cuproptosis. Here, we define the biological and pharmacologic determinants of ES-induced cuproptosis in vivo, guiding the design of a more effective and tolerable ES analog. We first established that pre-bound ES (ES-Cu) is more potent and pharmacologically active than ES alone, maintaining on-target cuproptosis activity in culture and showing superior efficacy in a xenograft model. Although ES-Cu treatment produced marked tumor responses, complete regression was not achieved. To uncover mechanisms limiting response, we performed a genome-scale ORF overexpression screen and identified CYP11A1 and CYP27A1, mitochondrial partners of FDX1, as resistance factors. These findings indicate that FDX1 expression alone is not sufficient for sensitivity and that effective cuproptosis requires FDX1 activity uncoupled from CYP metabolism, a relationship that may also protect FDX1-high organs such as the adrenal gland and kidney from toxicity. To further overcome ES's poor solubility and pharmacokinetic limitations, we synthesized a new copper ES analog, which exhibits improved solubility, enhanced antitumor efficacy, and reduced systemic toxicity. Multiplexed imaging confirmed intratumoral aggregation of lipoylated proteins consistent with on-target cuproptosis induction. Together, these findings uncover a previously unrecognized role of FDX1-CYP coupling in regulating cuproptosis sensitivity and define a path toward biomarker-guided development of copper ionophore-based cancer therapies.
利益披露 Disclosure
P. Mishra, None..
M. Banerjee, None..
J. Lin, None..
S. Coy, None..
J. Hsiao, None..
J. Lee, None..
J. Clohessey, None..
A. Detappe, None..
L. Charbonniere, None..
S. Santagata, None..
P. Tsvetkov, None.